Allergic diseases (AD) including allergic rhinitis, asthma and atopic dermatitis affect about 20% of the population and are important causes of morbidity and mortality. Most allergic diseases are found in association with immediate hypersensitivity to inhaled allergens and are associated with a familial tendency toward various forms of hypersensitivity, a condition known as atopy. The etiology of allergic diseases is unknown; however there are numerous cellular and humoral defects including a raised total IgE and multiple positive specific IgE antibodies to a wide range of allergens. Although many concepts of pathogenesis are currently explored, the general treatment of allergic diseases is still unsatisfactory. Immunosuppressants like steroid and cyclosporine have been administered to patients with clinical improvement. However, they have toxic effects on the hepatic and renal system. Therfore, the use of immunosuppressants in children has been reduced. Even with effective treatments which have significant side effects there is still a proportion of patients who are recalcitrant to all forms of drugs.
There is evidence that exposure to indoor allergens is a causative factor for the development of asthma among individuals who are genetically predisposed to make IgE antibody (ab) response. Allergens derived from house dust mites have been recognized as an important cause of IgE ab responses for over 30 years, and Dermatophagoides species (family Pyroglyphidae) are the predominant fauna in house dust worldwide. At least some groups of protein allergens have been defined and cloned Dermatophagoides spp, and used in etiological studies investigating the role of dust mite in asthma (1-7).
The main characteristic of the allergic diathesis is the propensity to develop a sustained immunoglobulin E (IgE) response to common environmental antigens (Ag) (8). IgE production is highly dependent on IL-4 and strongly inhibited by IFN-r. Other cytokines, such as IL-5, IL-6, IL-8, IL-12 and IL-13, as well as cell-surface molecules such as CD40 and CD23, may be involved (9-11). Recent studies using bronchoalveolar lavage fluids show that the production of IgE can be regulated by suppressor T cells (12). Furthermore, a successful outcome of immunotherapy has been associated with the development of suppressor T cells which can down-regulate the allergic responses (13). There is also evidence for a defect in suppressor T-cell function in atopic subjects, particularly children with allergic asthma. Recent data from animal experiments have also revealed that functionally distinct subsets of CD8.sup.+ T cells may play an important regulatory role in IgE production and suppress allergen-induced airway hyperresponsiveness (AHR) (14-17). It is therefore possible to generate Ag-specific suppressor T cells to modulate the IgE antibody response and AHR in atopic patients.
Previous methods of subunit vaccination have used purified proteins or viral vectors. Each of these methods has substantial limitations such as protein production and its purification procedures that would be overcome if the immunizing protein could be expressed in host cells. In this regard, gene vaccines represent a new approach to the development of subunit vaccines. The intramuscular injection of DNA has previously been shown to result in the expression of the protein encoded by the DNA (18-20). Furthermore, results indicate that the plasmid DNA persist episomally without replication or incorporation into the host cell genome (21). Serious inflammatory reactions at the site of inoculation or other complications have not been observed.
In addition, it is well established that peptides derived from intracellular Ags are generally presented to CD8.sup.+ T cells by major histocompatibility complex (MHC) class I molecules, which are expressed on virtually all somatic cells, while peptides derived from extracellular Ags are presented to CD4.sup.+ T cells by MHC class II molecules normally expressed by specialized, Ag-presenting cells (22).
Down-regulation of immune responses to inert nonpathogenic Ag is central to the maintenance of immunologic homeostasis at mucosal surfaces in the respiratory and gastrointestinal tracts, and failure of the underlying control mechanism(s) has been suggested as a key etiologic factor in allergic diseases. An important component of this process is the selective suppression of Th2-dependent IgE response to inhaled or fed Ags, which is mediated by Ag-specific CD8.sup.+ T cells (23).
Previous reports showed that CD8.sup.+ T cells, which have long been regarded simply as cytotoxic cells, play a more active role in the regulation of the immune response. CD8.sup.+ T cells may regulate IgE production by suppressing IgE synthesis via the inhibitory effect of IFN-r on B cells and/or by affecting the differentiation and function of Th2-like CD4.sup.+ T cells, which support IgE production. An alternative explanation may be that CD8.sup.+ T cells interact physically with B cells or CD4.sup.+ T cells and may provide suppressive signals through cognate interaction (24).
At present, it requires a means of introducing allergen into the endogenous Ag-processing pathway to induce the production of Ag-specific CD8.sup.+ T cells and inhibit allergen-specific IgE synthesis for the prevention and/or treatment of allergic disease.